A Heterogeneous Codonopsis pilosula Polysaccharide Preparation Attenuates Doxorubicin-Induced Cardiotoxicity in Mice: Associations with Oxidative Stress, Mitochondrial Function, and Gut Microbiota

Doxorubicin-induced cardiotoxicity remains a major limitation of anthracycline chemotherapy and is closely associated with oxidative stress and mitochondrial dysfunction. Here, we investigated whether a commercial Codonopsis pilosula polysaccharide preparation (CPP) could attenuate Dox-induced cardiac injury in mice. The preparation was characterized as a glucose-dominant heteropolysaccharide with a broad and heterogeneous molecular-weight distribution dominated by a lower-molecular-weight fraction (89.25% of the integrated chromatographic area; Mw = 1.64 kDa). CPP administration improved ejection fraction and fractional shortening and attenuated myocardial fibrosis and serum markers of cardiac injury. Histological and ultrastructural analyses showed preservation of myocardial architecture and mitochondrial integrity. CPP treatment was accompanied by increased SOD and GSH-PX activities, reduced MDA accumulation, partial recovery of mitochondrial respiratory-chain-related transcripts, and restoration of cardiac ATP content. In addition, 16S rRNA gene sequencing showed that high-dose CPP treatment was associated with partial reversal of Dox-induced gut-microbiota alterations, including increased microbial diversity, reduced Escherichia-Shigella, and increased norank_f__Muribaculaceae and Ligilactobacillus. Collectively, the tested heterogeneous CPP preparation attenuated Dox-induced cardiac injury and was accompanied by improved oxidative-stress indices, preserved mitochondrial structure and function, and changes in gut-microbiota composition.